Epitope-Specific Targeting of Tau Aggregates.

Tau 聚集体的表位特异性靶向。

• 批准号: 10187658
• 负责人: Einar M Sigurdsson
• 金额: $ 42.38万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10187658
• 关键词: Affinity; Alzheimer' s Disease; Amyloid beta-Protein; Antibodies; Antibody Affinity; Antigens; Attention; Binding; Brain; Cells; Charge; Chimera organism; Clinical Trials; Collaborations; Crystallization; Dementia; Development; Diagnostic; Disease; Disease model; Epitopes; Future; Human; Immunotherapy; Impaired cognition; Mediating; Monoclonal Antibodies; Mus; Mutation; Neuroglia; Neurons; Pathogenesis; Pathologic; Pathology; Pathway interactions; Phosphoserine; Property; Proteins; Proteomics; Public Health; Reporting; Research; Research Personnel; Site; Structure; Tauopathies; Testing; Therapeutic; Toxic effect; United States National Institutes of Health; Universities; Vaccines; antibody engineering; base; beta amyloid pathology; extracellular; improved; insight; interest; mimetics; prevent; programs; protein misfolding; small molecule; tau Proteins; tau aggregation; uptake

Tau immunotherapy for Alzheimer's disease and related tauopathies has advanced from proof-of- concept studies (Sigurdsson, EM, NIH R01AG020197, 2001; Asuni AA et al, J Neurosci, 27, 2007) to clinical trials. Because tau pathology correlates better with the degree of dementia than amyloid-β (Aβ) pathology, it is likely that targeting tau will be more effective than clearing Aβ in the later stages of the disease, when cognitive impairments are evident. Even though a few clinical trials have been initiated after confirmation and extension of the original studies, we have a very limited understanding of the mechanisms involved in antibody-mediated clearance of tau pathology. Some insight has been obtained on which epitopes to target and the mechanism of action but much remains to be clarified. Interestingly, tau antibodies interact with the protein both extra- and intracellularly but the importance of each site for tau clearance is not well defined, and is likely antibody-dependent. Some antibodies are readily taken up into neurons whereas others are not and these differences are likely charge- dependent. As most of tau is found intraneuronally, targeting it there is likely to be more efficacious than only outside neurons. The overall hypothesis of the project is that tau antibodies can slow the progression of tau pathology in humans. The Specific Aims are: 1) To determine how charge, isotype, affinity and size influence antibody efficacy and to clarify the mechanisms involved, and; 2) Antibody engineering based on structural characterization to improve efficacy and for humanization. Towards these aims, we have established collaborations with investigators at our university, who have complementary interests and expertise. The project will focus on antibodies against a key tau epitope, phospho-serine 396,404, which we targeted in our pioneering studies, and it has now been confirmed to be a feasible target by several groups. We will study how charge, isotype, affinity and size influence the efficacy. Furthermore, we will examine how antibody uptake and glial cells influence efficacy, assess proteomic changes associated with antibody- mediated clearance of tau pathology to identify the pathways involved, and engineer the antibodies to clarify mechanisms and improve efficacy. This program should advance our mechanistic understanding of tau immunotherapies and how those can be improved to treat Alzheimer's disease and related tauopathies, with direct relevance to various other protein misfolding disorders.

针对阿尔茨海默病和相关 tau 病的 Tau 免疫疗法已取得进展 概念研究（Sigurdsson, EM, NIH R01AG020197, 2001；Asuni AA 等人，J Neurosci, 27, 2007）到临床 由于 tau 蛋白病理学与痴呆程度的相关性高于 β 淀粉样蛋白 (Aβ) 病理学，因此， 在疾病的后期阶段，当认知能力下降时，靶向 tau 蛋白可能比清除 Aβ 更有效。 损伤是显而易见的。 尽管在原定方案的确认和延期后已经启动了一些临床试验 研究中，我们对抗体介导的清除所涉及的机制了解非常有限 tau 病理学已经获得了一些关于靶向表位和作用机制的见解，但 tau 抗体与细胞外和细胞内的蛋白质相互作用还有很多待澄清。 但每个位点对于 tau 清除的重要性尚未明确，并且可能依赖于抗体。 抗体很容易被神经元吸收，而其他抗体则不然，这些差异可能是电荷- 由于大多数 tau 蛋白存在于神经元内，因此靶向那里可能比仅靶向它更有效。 外部神经元。 该项目的总体假设是 tau 抗体可以减缓 tau 病理学的进展 具体目标是： 1) 确定电荷、同种型、亲和力和大小如何影响抗体。 功效并阐明所涉及的机制；2）基于结构的抗体工程 为了提高功效和人性化，我们建立了表征。 与我们大学的研究人员合作，他们具有互补的兴趣和专业知识。 该项目将重点关注针对关键 tau 表位磷酸丝氨酸 396,404 的抗体，我们 我们的开创性研究中的目标，现在已被多个团体证实是一个可行的目标。 我们将研究电荷、同种型、亲和力和大小如何影响功效。此外，我们将研究如何影响功效。 抗体摄取和神经胶质细胞影响功效，评估与抗体相关的蛋白质组变化 介导 tau 病理学清除，以确定所涉及的途径，并设计抗体来澄清 机制，提高效能。 该计划应能增进我们对 tau 免疫疗法的机制理解以及这些疗法如何 可以改进以治疗阿尔茨海默病和相关的 tau蛋白病，与其他各种疾病直接相关 蛋白质错误折叠障碍。